Sjogren's syndrome (keratoconjunctivitis sicca) serves as a prototype model for the study of human autoimmune disease due to safe access to the target organ (the minor salivary glands) and to the fluid draining from the inflamed organ (i.e., tears and saliva). We have continued our study of a cohort of 50 patients with Sjogren's syndrome and age matched controls in order to determine the immune regulatory factors associated with disease flares and response to medication. We plan to test the following hypotheses: a) salivary gland infiltrating lymphocytes have increased levels of bcl-x, resulting in decreased apoptosis of the autoimmune lymphocytes; b) glandular secretion is greatly diminished by the local production of TNF-alpha and IL-1, resulting in a linkage between immune events and neuro-secretory function; and c) fatigue in Sjogren's syndrome is partially mediated by TNF-alpha and IL-1. Using methods of protein assay and RNAse protection to measure mRNA, we will study the levels of IL-1, IL-1RA, TNF-a and TNF-receptor in patients' serum and tears. Based on results of current studies on a pre-clinical model of Sjogren's syndrome (the NOD.B10 mouse), we plan to study the role of a therapeutic inhibitor of TNF (sTNFR1) in patients during the next year.